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Oxidative stress and Parkinson’s disease

Javier Blesa, Ines Trigo-Damas, Anna Quiroga-Varela and 1 more

Frontiers in Neuroanatomy · 2015 · Review

doi:10.3389/fnana.2015.00091

Abstract

Parkinson disease (PD) is a chronic, progressive neurological disease that is associated with a loss of dopaminergic neurons in the substantia nigra pars compacta of the brain. The molecular mechanisms underlying the loss of these neurons still remain elusive. Oxidative stress is thought to play an important role in dopaminergic neurotoxicity. Complex I deficiencies of the respiratory chain account for the majority of unfavorable neuronal degeneration in PD. Environmental factors, such as neurotoxins, pesticides, insecticides, dopamine (DA) itself, and genetic mutations in PD-associated proteins contribute to mitochondrial dysfunction which precedes reactive oxygen species formation. In this mini review, we give an update of the classical pathways involving these mechanisms of neurodegeneration, the biochemical and molecular events that mediate or regulate DA neuronal vulnerability, and the role of PD-related gene products in modulating cellular responses to oxidative stress in the course of the neurodegenerative process.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 16, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

Parkinson’s disease (PD) is associated with the selective loss of dopamine (DA) neurons in the substantia nigra pars compacta (SNpc) and DA levels in the corpus striatum of the nigrostriatal DA pathway in the brain. This loss of DA causes a deregulation in the basal ganglia circuitries that leads to the appearance of motor symptoms such as bradykinesia, resting tremor, rigidity, and postural instability as well as non-motor symptoms such as sleep disturbances, depression, and cognitive deficits. The exact etiology of PD still remains elusive and the precise mechanisms that cause this disease remain to be identified. At the cellular level, PD is related to excess production of reactive oxygen species (ROS), to alterations in catecholamine metabolism, to modifications in mitochondrial electron transporter chain (METC) function or to enhancement of iron deposition in the SNpc. The failure of normal cellular processes that occur in relation to the aging process are also believed to contribute to the increased vulnerability of DA neurons.

While the familial forms of PD, that have been described, involve mutations in a number of genes, mitochondrial dysfunction, neuroinflammation and environmental factors are increasingly appreciated as key determinants of dopaminergic neuronal susceptibility in PD, and are a feature of both familial and sporadic forms of the disease. In both cases, oxidative stress is thought to be the common underlying mechanism that leads to cellular dysfunction and, eventual cell death. ROS are continuously produced in vivo by all body tissues. However, oxidative stress occurs when there is an imbalance between ROS production and cellular antioxidant activity. Oxidants and superoxide radicals are produced as products of oxidative phosphorylation, making mitochondria the main site of ROS generation within the cell. ROS can affect mitochondrial DNA which can cause modulations in the synthesis of METC components like adenosine triphosphate (ATP) production as well as the leakage of ROS into the cell’s cytoplasm.

Although the precise mechanism corresponding to ROS generation related to PD is still unknown, in this review, we summarize the major sources of oxidative stress generated by the DA neurons, like DA metabolism, mitochondrial dysfunction, and neuroinflammation (Figure 1).

Dopamine Metabolism

Selective degeneration of the DA neurons of the SNpc suggests that DA itself may be a source of oxidative stress. DA is synthesized from tyrosine by tyrosine hydroxylase (TH) and aromatic amino acid decarboxylase. Following this, DA is stored in synaptic vesicles after uptake by the vesicular monoamine transporter 2 (VMAT2). However, when there is an excess amount of cytosolic DA outside of the synaptic vesicle in damaged neurons, i.e., after L-DOPA treatment, DA is easily metabolized via monoamine oxidase (MAO) or by auto-oxidation to cytotoxic ROS. For example, mishandling of DA in mice with reduced VMAT2 expression was sufficient to cause DA-mediated toxicity and progressive loss of DA neurons.

This oxidative process alters mitochondrial respiration and induces a change in the permeability transition pores in brain mitochondria. Also, the auto-oxidation of DA produces electron-deficient DA quinones or DA semiquinones. Some studies have demonstrated a regulatory role for quinone formation in DA neurons in the L-DOPA-treated PD model induced by neurotoxins and in methamphetamine neurotoxicity. DA quinones can modify a number of PD-related proteins, such as α-synuclein (α-syn), parkin, DJ-1, Superoxide dismutase-2 (SOD2), and UCH-L1 and have been shown to cause inactivation of the DA transporter (DAT) and the TH enzyme, as well as mitochondrial dysfunction, alterations of brain mitochondria and dysfunction in Complex I activity. Additionally, DA quinones can be oxidized to aminochrome, whose redox-cycling leads to the generation of the superoxide radical and the depletion of cellular nicotinamide adenine dinucleotide phosphate-oxidase (NADPH), which ultimately forms the neuromelanin known to be accumulated in the SNpc of the human brain.

Significant increases in cysteinyl adducts of L-DOPA, DA, and DOPAC have been found in substantia nigra of PD patients, suggesting the cytotoxic nature of DA oxidation. Also, DA terminals actively degenerated proportionally to increased levels of DA oxidation following a single injection of DA into the striatum. Recently, it has been shown that increased uptake of DA through the DAT in mice results in oxidative damage, neuronal loss and motor deficits.

Mitochondrial Dysfunction

Mitochondrial dysfunction is closely related to increased ROS formation in PD. Oxidative phosphorylation is the main mechanism providing energy to power neural activity in which the mitochondria use their structure, enzymes, and energy released by the oxidation of nutrients to form ATP. Consequently, this metabolic pathway is the main source of superoxide and hydrogen peroxide, which, at the same time, lead to propagation of free radicals contributing to the disease.

Complex I deficiencies of the respiratory chain account for the majority of unfavorable neural apoptosis generation and is considered one of the primary sources of ROS in PD. Complex I inhibition results in an enhanced production of ROS, which, in turn, will inhibit complex I. Reduction in complex I activity in the SNpc of patients with sporadic PD has been well described. Additionally, mitochondrial complex I deficiency in different brain regions, fibroblasts, blood platelets, skeletal muscle, and lymphocytes of PD patients has been shown before as well.

As such, complex I inhibitors like 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or rotenone show preferential cytotoxicity to the DA neurons. The mechanism by which MPTP crosses the blood–brain barrier and is oxidized to 1-methyl-4-phenylpyridinium (MPP+) is well known. The MPP+ accumulates in the mitochondria where it inhibits complex I in the METC, therefore disrupting the flow of electrons along the METC, which results in decreased ATP production and increased generation of ROS. Like MPTP, rotenone is another mitochondrial complex I inhibitor. Interestingly, rotenone toxicity is involved in oxidative damage to proteins and Lewy body-like inclusions. The events downstream to complex I inhibition that lead to neuronal cell death by these toxins are still unknown.

Other evidence for mitochondrial dysfunction related to oxidative stress and DA cell damage comes from findings that mutations in genes of proteins like α-syn, parkin, DJ-1, or PINK are linked to familial forms of PD. The convergence of all of these proteins on mitochondrial dynamics uncovers a common function in the mitochondrial stress response that might provide a potential physiological basis for the pathology of PD. Overall, these observations show that mutations in these genes affect mitochondrial function and integrity and, are associated with increases in oxidative stress. ROS influence proteasomal, lysosomal, and mitochondrial function, which, in turn, regulate the cellular response to oxidative damage. The correct elimination of damaged proteins by effective proteolysis and the synthesis of new and protective proteins are vital in the preservation of brain homeostasis during periods of increased levels of ROS. Consequently, this can lead to protein misfolding (i.e., α-syn), preventing the ability of some of these proteins to be unfolded and degraded by the systems that regulate protein clearance, like the ubiquitin proteasome system or autophagy. Indeed, protein misfolding, together with the dysfunction of these protein degradation systems, may play a key role in the appearance of deleterious events implicated in the neurodegenerative process of PD.

Parkin and PINK1 are localized in the mitochondria and their functions are tightly connected to the normal functioning of the mitochondria. PINK1 accumulates on the outer membrane of damaged mitochondria and recruits Parkin to the dysfunctional mitochondrion. In humans with parkin mutations, mitochondrial complex I activity is impaired. Overexpression of parkin in mice reduced DA neuronal cell loss induced by MPTP through the protection of mitochondria and the reduction of α-syn. On the other hand, parkin KO mice showed decreased amounts of several proteins that are involved in mitochondrial function and oxidative stress as well as increases in protein oxidation and lipid peroxidation. Also, Drosophila, lacking, or deficient in parkin, exhibit mitochondrial deficits and high vulnerability to oxidative stress. PINK1 mutations in humans lead to mitochondrial defects and respiratory chain abnormalities. PINK1 KO in human and mouse DA neurons causes decreases in membrane potential and increases in ROS generation. The decrease in mitochondrial membrane potential is not due to a proton leak, but to respiratory chain defects like complex I and complex III deficiency. Therefore, PINK1 is required for maintaining normal mitochondrial morphology of SNpc DA neurons in culture and exerts its neuroprotective effect by inhibiting ROS formation. In animal models, studies show that the lack of PINK1 resulted in abnormal mitochondrial morphology, loss of SNpc DA neurons, reduction in complex I activity, and enhanced vulnerability to oxidative stress. These defects can be ameliorated and rescued by the enhanced expression of parkin. This last scenario seems to involve PINK1 and Parkin in a common pathway that regulates mitochondrial physiology and cell survival in which PINK1 seems to be functioning upstream of Parkin, at least as observed in Drosophila disease models.

α-syn is a soluble protein that is highly enriched in the presynaptic terminals of neurons. Accumulation of α-syn as intracellular filamentous aggregates is a pathological feature of both sporadic and familial PD. Accumulation of wild-type α-syn in DA neurons reduced mitochondrial complex I activity, elevated ROS production leading to cell death. It has been shown that α-syn inclusions elevate dendritic mitochondrial oxidative stress in DA neurons. This mitochondrial dysfunction occurs many months before the occurrence of striatal DA loss. The nuclear translocation of α-syn increases susceptibility of MES23.5 cells to oxidative stress. Exposure to rotenone or other stimuli that promote ROS formation and mitochondrial alterations correlate well with mutant α-syn phosphorylation at Ser129. Oxidative stress promotes uptake, accumulation, and oligomerization of extracellular α-syn in oligodendrocytes and induces posttranslational modifications of α-syn which can increase DA toxicity. It has been suggested that the NADPH oxidases, which are responsible for ROS generation, could be major players in synucleinopathies.

DJ-1 is another gene reported to cause a familial early onset PD. DJ-1 binds to subunits of mitochondrial complex I and regulates its activity. Although a portion of DJ-1 is present in mitochondria matrix and inter-membrane space, the degree of translocation of DJ-1 into mitochondria is stimulated by oxidative stress. Mitochondrial-targeted sequence-conjugated DJ-1 has been shown to be more protective against oxidative stress-induced cell death. DJ-1 KO mice displayed nigrostriatal DA neuron loss. Also, these DJ-1 KO mice showed altered mitochondrial respiration and morphology, reduced membrane potential, and accumulation of defective mitochondria. These defects can be reversed by DJ-1 overexpression, which points to the specific role of DJ-1 in mitochondrial function. Recently, following oxidative stress, DJ-1 was shown to be involved in the oxidative stress response that leads to the upregulation of the proteasome, thus inhibiting its activity and rescuing partially unfolded proteins from degradation.

Neuroinflammation

Neuronal loss in PD is associated with chronic neuroinflammation, which is controlled primarily by microglia, the major resident immune cells in the brain and, to a lesser extent, by astrocytes and oligodendrocytes. Microglial activation has been found with a greater density in the SNpc and in the olfactory bulb of both sporadic and familial PD patients. Additionally, activated microglia have been found in the SNpc and in the striatum of PD animal models and have been associated with different PD-associated gene/proteins like α-syn or LRRK2. In response to certain environmental toxins and endogenous proteins, microglia can shift to an over-activated state and release ROS which can cause neurotoxicity. Accumulating evidence indicates that activation of different enzymes like NADPH oxidase (NOX2) in microglia is neurotoxic not only through the production of extracellular ROS that damage neighboring neurons but also through the initiation of redox signaling in microglia that amplifies the pro-inflammatory response.

Neuromelanin confers the dark pigmentation that is produced from DA oxidation and is so characteristic of the SNpc appearance. High levels of catecholamine metabolism in the midbrain are associated with increased levels of neuromelanin in the same region and, it is neuromelanin that is thought to be one of the molecules responsible for inducing chronic neuroinflammation in PD. Neuromelanin released from dying DA neurons in the SNpc activate microglia, increasing the sensitivity of DA neurons to oxidative stress-mediated cell death. The ability of neuromelanin to interact with transition metals, especially iron, and to mediate intracellular oxidative mechanisms have received particular attention. Increased levels of iron result in increased ROS and increased oxidative stress and has been shown to be involved in aging and PD. Iron homeostasis is modulated by angiotensin in DA neurons and microglia, and glial cells play an essential role in the efficient regulation of this balance.

Dopamine neurons containing neuromelanin are especially more susceptible, indicating a possible role for neuromelanin in MPTP-toxicity. MPTP induces a glial response, increased levels of inflammatory cytokines and microglial activation in mice and monkeys. Angiotensin is one of the most important inflammation and oxidative stress inducers, and produces ROS by activation of the NADPH-oxidase complex. It has been suggested that the inflammatory response in the MPTP model could be mediated by brain angiotensin and microglial NADPH-derived ROS. Moreover, oral treatment with NADPH oxidase antagonists mitigates the clinical and pathological features of parkinsonism in the MPTP marmoset model. Also, microglia play an important role in mediating rotenone-induced neuronal degeneration through NADPH. Rotenone increased microglial activation in both the SNpc and striatum in rats, activated microglia via the NF-κB signaling pathway and induced neuronal death by the microglial phagocytosis of neurons.

Parkinson’s disease-associated proteins like α-syn, parkin, LRRK2, and DJ-1 have also been reported to activate microglia. Extracellular α-syn released from neuronal cells is an endogenous agonist for Toll-like receptor 2 (TLR2), which activates the microglial inflammatory responses. An increased number of activated microglia and increased levels of TNF-α mRNA and protein were detected in the striatum and in the SNpc of mice over-expressing WT human α-syn. Moreover, in α-syn KO mice, microglia secreted higher levels of proinflammatory cytokines, TNF alpha and IL-6 (interleukin-6) compared to WT mice. Intracerebral injection of recombinant amyloidogenic or soluble α-syn induces extensive α-syn intracellular inclusion pathology that is associated with a robust gliosis. LRRK2 increases proinflammatory cytokine release from activated primary microglial cells which results in neurotoxicity. In contrast, LRRK2 inhibition attenuates microglial inflammatory responses. Additionally, lipopolysaccharide induces LRRK2 up-regulation and microglial activation in mouse brains but they down regulated Parkin expression via NF-κB. Abnormal glial function is critical in parkin mutations, increasing vulnerability to inflammation-related nigral degeneration in PD and its role increases with aging. DJ-1 expression is up-regulated in reactive astrocytes in PD patients. DJ-1 negatively regulates inflammatory responses of astrocytes and microglia by facilitating the interaction between STAT1 and its phosphatase SHP-1. Astrocyte cultures from DJ-1 KO mice treated with lipopolysaccharide have increased NO production and an up-regulation of different pro-inflammatory mediators like COX-2 and IL-6.

Conclusion

The elements that potentially cause oxidative stress in PD are still unknown. DA metabolism, mitochondrial dysfunction and neuroinflammation all play critical roles in the etiology of this disease. Exposure to environmental factors or mutations in PD-associated genes of patients with either sporadic or familial PD may cause mitochondrial dysfunction that ultimately results in PD. All of these share common linkages and influence each other greatly. Limiting the early inflammatory response will reduce further both elevated oxidative stress and microglial activation that are key to slowing the death of the neurons in the SNpc. Development of potential drugs able to delay the neurodegenerative process is crucial to ameliorating the deleterious effects of oxidative stress in neurodegenerative diseases. Neuroprotective therapies will need to target multiple pathological pathways such as mitochondrial dysfunction and neuroinflammation in the next few years.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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